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Cell. 2016 Aug 11;166(4):920-934. doi: 10.1016/j.cell.2016.07.003. Epub 2016 Aug 4.

Glycosylation-Dependent IFN-γR Partitioning in Lipid and Actin Nanodomains Is Critical for JAK Activation.

Author information

1
Institut Curie, PSL Research University, CNRS UMR3666, INSERM U1143, 75005 Paris, France.
2
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France.
3
Centre de Physiologie Toulouse-Purpan (CPTP), INSERM U1043, 31300 Toulouse, France.
4
Institut des Maladies Métaboliques et Cardiovasculaires, Université Toulouse III Paul Sabatier, INSERM U1048, 31432 Toulouse, France.
5
Institut Fresnel, Aix Marseille Université, Centrale Marseille, CNRS, Marseille, France.
6
Proteomics and Mass Spectrometry Laboratory, Institut Curie, PSL Research University, 75005 Paris, France.
7
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Hospital for Sick Children, Imagine Institute, INSERM UMR1163, 75015 Paris, France; University Paris Descartes, 75006 Paris, France.
8
Instituto Biofísica (UPV/EHU, CSIC), P.O. Box 644, 48080 Bilbao, Spain; Departamento de Bioquímica y Biologia Molecular, Universidad del País Vasco, P.O. Box 644, 48080 Bilbao, Spain; IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain.
9
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Hospital for Sick Children, Imagine Institute, INSERM UMR1163, 75015 Paris, France; University Paris Descartes, 75006 Paris, France; Howard Hughes Medical Institute, New York, NY 10065, USA; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France.
10
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France. Electronic address: he@ciml.univ-mrs.fr.
11
Institut Curie, PSL Research University, CNRS UMR3666, INSERM U1143, 75005 Paris, France. Electronic address: christophe.lamaze@curie.fr.

Abstract

Understanding how membrane nanoscale organization controls transmembrane receptors signaling activity remains a challenge. We studied interferon-γ receptor (IFN-γR) signaling in fibroblasts from homozygous patients with a T168N mutation in IFNGR2. By adding a neo-N-glycan on IFN-γR2 subunit, this mutation blocks IFN-γ activity by unknown mechanisms. We show that the lateral diffusion of IFN-γR2 is confined by sphingolipid/cholesterol nanodomains. In contrast, the IFN-γR2 T168N mutant diffusion is confined by distinct actin nanodomains where conformational changes required for Janus-activated tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) activation by IFN-γ could not occur. Removing IFN-γR2 T168N-bound galectins restored lateral diffusion in lipid nanodomains and JAK/STAT signaling in patient cells, whereas adding galectins impaired these processes in control cells. These experiments prove the critical role of dynamic receptor interactions with actin and lipid nanodomains and reveal a new function for receptor glycosylation and galectins. Our study establishes the physiological relevance of membrane nanodomains in the control of transmembrane receptor signaling in vivo. VIDEO ABSTRACT.

PMID:
27499022
DOI:
10.1016/j.cell.2016.07.003
[Indexed for MEDLINE]
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